The invention relates to cyclic and heterocyclic N-substituted xcex1-iminohydroxamic and -carboxylic acids, to processes for their preparation and to their use as pharmaceuticals.
EP 0 606 046 discloses some arylsulfonamidohydroxamic acid derivatives and their action as matrix metalloproteinase inhibitors.
In the effort to find further efficacious compounds for the treatment of connective tissue disorders, it has now been found that the iminohydroxamic acid derivatives according to the invention are inhibitors of metalloproteinases.
The invention relates to a compound of the formula I 
and/or an optionally stereoisomeric form of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I, where in the case i)
R1 is
a) a radical of the formula II 
b) a radical of the formula III 
c) a radical of the formula IV 
where Z is a radical of a heterocycle or a substituted heterocycle such as
1) pyrrole,
2) thiazole,
3) pyrazole,
4) pyridine,
5) imidazole,
6) pyrrolidine,
7) piperidine,
8) thiophene,
9) oxazole,
10) isoxazole,
11) morpholine or
12) piperazine,
d) naphthyl,
e) naphthyl, mono- or trisubstituted by R2, or
f) a radical of the formula V 
xe2x80x83where o is the number 1 or 2 and one of the carbon atoms in the ring may be replaced by xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and
Q as part of the structural formula I 
R2 is
1) phenyl or
2) phenyl which is mono- to trisubstituted by
2.1 hydroxyl,
2.2 xe2x80x94Oxe2x80x94R10 where R10 
1) is (C1-C6)-alkyl,
2) is (C3-C6)-cycloalkyl,
3) is benzyl or
4) is phenyl,
2.3 xe2x80x94COOH,
2.4 (C1-C6)-alkyl,
2.5 (C3-C6)-cycloalkylxe2x80x94Oxe2x80x94(C1-C4)-alkyl,
2.6 halogen,
2.7 xe2x80x94CN,
2.8 xe2x80x94NO2,
2.9 xe2x80x94CF3,
2.10 xe2x80x94Oxe2x80x94C(O)xe2x80x94R10 and R10 is as defined above,
2.11 xe2x80x94Oxe2x80x94C(O)-phenyl, mono- or disubstituted by R3,
2.12 xe2x80x94C(O)xe2x80x94Oxe2x80x94R10 and R10 is as defined above,
2.13 methylenedioxo,
2.14 xe2x80x94C(O)xe2x80x94NR11R12, where R11 and R12 may be identical or different and each is
1) a hydrogen atom,
2) (C1-C4)-alkyl or
3) benzyl or
4) R11 and R12 together with the linking nitrogen atom form a pyrrolidine, piperidine, morpholine or oiperazine radical, or
2.15 NR13R14, where R13 is a hydrogen atom or (C1-C4)-alkyl and
R14 
1) is a hydrogen atom,
2) is (C1-C4)-alkyl,
3) is benzyl,
4) is xe2x80x94C(O)xe2x80x94R10 or
5) is xe2x80x94C(O)xe2x80x94Oxe2x80x94R10,
R3 and R4 are identical or different and each is
1) a hydrogen atom,
2) (C1-C5)-alkyl,
3) (C1-C5)-alkoxy,
4) halogen,
5) hydroxyl,
6) xe2x80x94Oxe2x80x94C(O)xe2x80x94R10 and R10 is as defined above, or
7) R3 and R 4together form the radical xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94,
R5 is
a) a hydrogen atom,
b) (C1-C5)-alkyl or
c) benzyl, and
R6, R7 and R8 are identical or different and each is
a) a hydrogen atom, or
b) has, in the case of i), the meaning of R2 under items 2.1 to 2.14, and
n is zero, 1 or 2,
m is zero, 1 or 2, the sum of n and m being 1, 2 or 3, or
where in the case ii)
R1 is
1) phenyl or
2) phenyl, mono- to trisubstituted by R2, where R2 is as defined for the case i) under items 2.1 to 2.15,
Q is the structural moiety X and
R6, R7 and R8 are identical or different and each is defined as above,
n is 1 and
m is 1, or
where in the case iii)
R1, Q, R6, R7 and R8 are identical or different and each has the meaning mentioned for the case ii),
m and n are zero, 1 or 2 and where the meanings of n and m are not identical, and
X is
a) a covalent bond,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94Sxe2x80x94,
d) xe2x80x94S(O)xe2x80x94,
e) xe2x80x94S(O)2xe2x80x94,
f) xe2x80x94C(O)xe2x80x94 or
g) xe2x80x94C(OH)xe2x80x94, and
Y is
a) xe2x80x94Oxe2x80x94 or
b) xe2x80x94Sxe2x80x94, and
A is HOxe2x80x94NHxe2x80x94C(O)xe2x80x94 or HOxe2x80x94C(O)xe2x80x94 and
B is
a) xe2x80x94(CH2)qxe2x80x94, where q is zero, 1, 2, 3 or 4, or
b) is xe2x80x94CHxe2x95x90CHxe2x80x94.
Preference is given to a compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where
R1 in the case i) is a radical of the formula II or III and Q is the structural moiety VI, VII, VIII or X,
R1 in the case ii) is phenyl or phenyl, mono- to trisubstituted by methoxy, and Q is the structural moiety X, or
R1 in the case iii) is phenyl, Q is the structural moiety X, n is zero and m is 2, and
A is HOxe2x80x94NHxe2x80x94C(O)xe2x80x94 or HOxe2x80x94C(O)xe2x80x94,
B is a covalent bond,
X is an oxygen atom or a covalent bond, and
R2 is phenyl or phenyl substituted by
a) hydroxyl,
b) xe2x80x94Oxe2x80x94R10, where R10 is (C1-C3)-alkyl or benzyl,
c) (C1-C2)-alkyl,
d) fluorine or chlorine,
e) xe2x80x94CN,
f) xe2x80x94CF3 or
g) NR13R14, where R13 and R14 are each (C1-C3)-alkyl,
R3, R4, R5, R6, R7 and R8 are identical or different and each is
a) a hydrogen atom,
b) methoxy,
c) methylenedioxo,
d) amino or
e) hydroxyl.
Particular preference is given to the compounds
R-2-(biphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-phenoxybenzenesulfonyl)1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-phenoxybenzenesulfonyl)1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-(4-dimethylaminophenoxy)benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-dimethylaminobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
R-2-(4-benzoylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
2-(4-methoxybenzenesulfonyl)-6,7-propylene-1,2,3,4-tetrahydroisoquinoline-1-hydroxamic acid,
R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1 H-imidazo-(4,5-c)-pyridine-6-hydroxamic acid,
R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamic acid,
R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamic acid.
Furthermore, particular emphasis is given to those compounds of the formula I where the central carbon atom between amino and acid group is present as R enantiomer.
The term halogen is understood as meaning fluorine, chlorine, bromine or iodine. The term alkyl or alkoxy is understood as meaning radicals whose carbon chain may be straight-chain, branched or cyclic. Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The xe2x80x9cheterocycles of the formula Vxe2x80x9d include, for example, thiomorpholine, piperidine, morpholine or piperazine.
Suitable physiologically tolerable salts of the compound of the formula I are, for example, alkali metal, alkaline earth metal and ammonium salts including those of organic ammonium bases or basic amino acids.
The invention also provides a process for preparing the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I which comprises
a) reacting an imino acid of the formula XI 
xe2x80x83where the radical Q and n and m are as defined in the formula I with a (C1-C4)-alcohol or a benzyl alcohol to give the compound of the formula XII 
where Rx is (C1-C4)-alkyl or benzyl, or
b) reacting a compound of the formula XII prepared according to process a) with the compound of the formula XIII 
xe2x80x83where R1 is as defined in formula I and RZ is a chlorine atom, imidazolyl or xe2x80x94OH, in the presence of a base or, if appropriate, a dehydrating agent to give a compound of the formula XIV 
xe2x80x83where Q, R1, n and m are as defined in formula I and Rx is as defined in formula XII, or
c) reacting a compound of the formula XII prepared according to process a) with a base and subsequently with a compound of the formula XIII to give a compound of the formula XIV, or
d) reacting a compound of the formula XI with a compound of the formula XIII to give a compound of the formula XV 
xe2x80x83where Q, R1, n and m are as defined in formula I, or
e) reacting a compound of the formula XIV to give a compound of the formula XV, or
f) reacting a compound of the formula XIV prepared according to process b) or c) with the hydroxylamine of the formula XVI
H2Nxe2x80x94ORyxe2x80x83xe2x80x83(XVI) 
xe2x80x83where Ry is a hydrogen atom or a protective group for oxygen, to give the compound of the formula I and, if appropriate, removing the protective group for oxygen, or
g) reacting a compound of the formula XV prepared according to process d) or e) with the hydroxylamine of the formula XVI to give the compound of the formula I, or
h) separating into the pure enantiomers a compound of the formula I prepared according to process f) or g) which, owing to its chemical structure, exists in enantiomeric forms, by forming salts with enantiomerically pure acids or bases, chromatography using chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the resulting diastereomers, and removal of the chiral auxiliary, or
i) isolating the compound of the formula I prepared according to processes f), g) or h) either in free form or, if acidic or basic groups are present, converting it, if appropriate, into physiologically tolerable salts.
In the case of the (C1-C4)-alcohols, the reaction according to process step a) is carried out under customary reaction conditions in the presence of HCl gas or thionyl chloride. The preparation of the corresponding benzyl esters of the formula XII is carried out in benzene or toluene using the appropriate alcohol and an acid such as p-toluenesuifonic acid. Tert-butyl esters can be prepared, for example, by known processes using isobutene and sulfuric acid.
The reaction according to process step b) is carried out in the presence of a basic compound such as N-methylmorpholine (NMM), N-ethylmorpholine (NEM), triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, collidine, imidazole or sodium carbonate in solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, dioxane, acetonitrile, toluene, chloroform or methylene chloride, or even in the presence of water. Preference is given to using the sulfonyl chlorides of the formula XII in the presence of NMM in THF.
The reaction according to process step c) is carried out in the presence of a base such as KOH, LiOH or NaOH.
The reaction according to process step d) is carried out in an aqueous organic solvent system, preferably in THF and water in the presence of a base such as sodium carbonate and the compound of the formula XIII. Furthermore, the reaction can be carried out in the absence of solvent with or without base under reduced pressure, as obtained by use of an oil pump.
The hydrolysis of the compound of the formula XIV to give the compound of the formula XV (process step e) is carried out, for example, basic, preferably acidic or, in the case of the benzyl derivatives, by hydrogenolysis. In the case of basic hydrolysis, it is necessary to free the carboxylic acid from the carboxylic acid salt by treatment with another acid, for example dilute hydrochloric acid.
The reaction according to process step f) is carried out under the conditions which are customary for the formation of carboxamides, in a suitable solvent, for example an alcohol or dimethylformamide.
For the reaction according to process step g), the carboxylic acids of the formula XV are activated. Activated carboxylic acids are, for example, acyl halides, acyl azides, mixed anhydrides and carbonates. Preference is given to acyl chlorides or fluorides, mixed anhydrides and carbonates of pivaloyl chloride, ethyl, isopropyl or isobutyl chioroformate; active esters such as cyanoethyl, o- or p-nitrophenyl, succinimido or phthalimido, and to the activated carboxylic acids which are obtainable using coupling reagents such as diisopropylcarbodiimide (DIC), carbonyidiimidazole (CDI), dicyclohexylcarbodimide (DCC) or benzotriazolyltetramethyluronium tetrafluoroborate (TBTU), if appropriate with addition of hydroxybenzotriazole (HObt) or oxohydroxybenzotriazine (HOObt), preferred solvents being aprotic solvents.
The starting materials and reagents employed can either be prepared by known processes, or they are commercially available.
Suitable imino acids of the formula XI where n and m are 1 its, for example, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-carboxylic acid or optionally 1- or 3-substituted 4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylic acids. They are preferably prepared by cyclizing the corresponding amino acids with formaldehyde in the presence of an acid such as hydrochloric acid or sulfuric acid using the method of Pictet-Spengler (see W. M. Whaley, Organic Reactions 6 (1951) 151.
In the case that in the imino acid of the formula XI n is zero and m is 2, it is possible to use, for example, 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indol-1-carboxylic acid and 6,7-propylene-1,2,3,4-tetraisoquinoline-1-carboxylic acid as starting material. To prepare the latter compound, indane is Friedel-Crafts alkylated with phenylsulfonylarziridine. The cyclization of the resulting 4-(2-benzenesulfonamidoethyl)indane is carried out using glyoxylic acid in HBr/glacial acetic acid; the subsequent cleavage of the benzenesulfonyl radical is carried out using iodine/red phosphorus in HBr/glacial acetic acid.
An example of the case where in the compound XI n is 1 and m is zero is indoline-2-carboxylic acid. It is prepared, for example, by catalytic hydrogenation of indol-2-carboxylic acid. Furthermore, mention may be made of the cyclization of 2-chlorophenylalanine or 2-hydroxy-3-(2-chlorophenyl)-propionic acid to give imino acids of the formula XI.
If compounds of the formula I permit diastereomeric or enantiomeric forms and are obtained as mixtures thereof in the synthesis chosen, separation into the pure stereoisomers is possible either by chromatography over an optionally chiral carrier material or, if the racemic compound of the formula I or a compound of the formula XI is capable of forming salts, by fractional crystallization of the diastereomeric salts formed with an optically active base or acid as auxiliary. Suitable chiral stationary phases for thin-layer- or column-chromatographic separation of enantiomers are, for example, modified silica carriers (Pirkle phases) and high-molecular-weight carbohydrates such as triacetylcellulose. For analytical purposes, gas-chromatographic methods using chiral stationary phases may also be used, after appropriate derivatization known to the person skilled in the art. The enantiomers of racemic carboxylic acids are separated using an optically active, usually commercially available base such as (xe2x88x92)-nicotine, (+)- and (xe2x88x92)-phenylethylamine, quinine bases, L-lysine or L- and D-arginine to form the diastereomeric salts, which differ in solubility. The less soluble component is isolated as a solid, the more soluble diastereomer is recovered from the mother liquor, and the pure enantiomers are obtained from the resulting diastereomeric salts. In basically the same manner, the racemic compounds of the formula I which contain a basic group such as an amino group can be converted into the pure enantiomers using optically active acids such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+) and (xe2x88x92)-mandelic acid. It is also possible to convert chiral compounds containing alcohol or amine functions into the corresponding esters or amides using appropriately activated or optionally n-protected enantiomerically pure amino acids, or, conversely, to convert chiral carboxylic acids into the amides using carboxyl-protected enantiomerically pure amino acids, or into the corresponding chiral esters using enantiomerically pure hydroxycarboxylic acids such as lactic acid. The chirality of the enantiomerically pure amino acid or alcohol radical can then be employed to separate the isomers by resolving the diastereomers that are now present using crystallization or chromatography over suitable stationary phases and then removing the chiral moiety which has been carried along by means of suitable methods.
Acidic or basic products of the compound of the formula I may be present in the form of their salts or in free form. Preference is given to pharmacologically tolerable salts, for example alkali metal or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of the amino acids, natural bases or carboxylic acids.
Hydroxylamine can be employed in free form, obtainable from hydroxylamine salts and a suitable base in solution or in O-protected form, or in each case also in the form of its salts. The preparation of free hydroxylamine is known from the literature and can be carried out, for example, in alcoholic solution. Preference is given to using the hydrochloride together with alkoxides such as Na methoxide, potassium hydroxide or potassium t-butoxide.
O-protected hydroxylamine derivatives preferably contain protective groups which can be removed under mild conditions. Particular preference is given here to protective groups of the silyl, benzyl and acetal types. Particularly suitable for this purpose are the O-trimethylsilyl, O-tert-butyidimethylsilyl, O-benzyl, O-tert-butyl and the O-tetrahydropyranyl derivative.
Starting materials and intermediates which are employed for preparing the compound of the formula I may, if they contain functional groups such as hydroxyl, thiole, amino or carboxyl, for example in the radicals R1, R2, R3, R4, R5, R6, R7 and R8, be employed in suitably protected form.
The introduction of protective groups is required in all those cases where, in a desired chemical reaction, undesirable side-reactions are to be expected at other locations than reaction centers (T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991).
The protective groups employed can be removed before or after the conversion of the compound of the formula XII into the compound of the formula I.
Particularly suitable for use as auxiliaries and bases are: HObt, HOObt, N-hydroxysuccinamide (HOSu), TEA, NMM, NEM, DIPEA, imidazole. Preferred solvents for the reaction are: dichloromethane (DCM), THF, acetonitrile, N,N-dimethylacetamide (DMA), DMF and N-methylpyrrolidone (NMP).
The preferred temperatures are between xe2x88x9278xc2x0 C. and +90xc2x0 C., depending on the boiling point and the nature of the solvent used. Particular preference is given to the temperature range from xe2x88x9220 to +30xc2x0 C.
The preparation of physiologically tolerable salts from compounds of the formula I which are capable of forming salts, including their stereoisomeric forms, is carried out in a manner known per se. The carboxylic acids and hydroxamic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or else basic amino acids, for example lysine, ornithine or arginine. If the compounds of the formula I have basic groups, it is also possible to prepare stable acid addition salts by using strong acids. Suitable for this purpose are both inorganic and organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid.
The invention also relates to pharmaceuticals which contain an effective amount of at least one compound of the formula I and/or of a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, together with a pharmaceutically suitable and physiologically tolerable excipient, additive and/or other active compounds and auxiliaries.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in the course of which is involved an increased activity of matrix-degrading metalloproteinases. These include degenerative joint disorders such as osteoarthroses, spondyloses, chondrolysis after joint traumas or relatively long immobilization of the joint after meniscus or patella injuries or tears of the ligaments. Furthermore, these also include disorders of the connective tissue such as collagenoses, periodontal disorders, wound healing disorders and chronic disorders of the locomotory apparatus such as inflammatory, immunologically or metabolically related acute and chronic arthritides, arthropathies, myalgias and disorders of the bone metabolism. The compounds of the formula I are also suitable for the treatment of ulceration, atherosclerosis and stenoses. The compounds of the formula I furthermore suppress the release of the cellular tumor necrosis factor (TNFxcex1) to a considerable extent and are therefore suitable for the treatment of inflammations, carcinomatous disorders, formation of tumor metastases, cachexia, anorexia and septic shock.
The pharmaceuticals according to the invention are in general administered orally or parenterally. Rectal or transdermal administration is also possible.
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, other suitable active compounds, additives or auxiliaries.
Suitable solid pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and also preparations with protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably prepared and administered in dose units, each unit as active constituent containing a specific dose of the compound of the formula I according to the invention. In solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be up to approximately 1000 mg, but preferably approximately 50 to 300 mg, and in injection solutions in ampoule form up to approximately 300 mg, preferably approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kgxe2x80x94depending on the efficacy of the compounds according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, preferably approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, higher or lower daily doses may be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at specific intervals.
1H-NMR spectra have been recorded on a 200 MHz apparatus from Varian, in general using tetramethylsilane (TMS) as an internal standard and at room temperature (RT). The solvents used are indicated in each case. Generally, final products are determined by mass spectroscopic methods (FAB-, ESI- MS). Temperature data in degrees Celsius, RT means room temperature (22xc2x0 C.-26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.